The present invention provides an accelerated process for preparing a O-methyl phenol (anisole), N-methyl heteroaromatic compound, or a methyl aminophenol, comprising reacting a phenol, an NH-containing heteroaromatic compound, or an aminophenol having at least one Nxe2x80x94H, with dimethyl carbonate in the presence of a catalyst selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); 1,4-diazabicyclo[2.2.2]octane (DABCO); and dimethylaminopyridine (DMAP).
Methylation of alcohols and amines is an important process in chemistry. However, due to the environmental and human impact of using toxic and unsafe methylating reagents such as methyl iodide or dimethyl sulfate, the investigation of safer, generally applicable alternatives continues. As an alternative to these toxic methylating agents, dimethyl carbonate (DMC) has attracted considerable attention for the methylation of phenols, anilines, and activated methylenes. DMC is non-toxic and generates CO2 and methanol as by-products during methylations. DMC is also a volatile liquid with a boiling point of 90xc2x0 C. Hence, the unreacted DMC can be easily recovered by distillation from the reaction mixture and reused. Furthermore, DMC has been shown to be quite selective in monomethylation of primary aromatic amines and C-methylation of arylacetonitriles and arylacetoesters.
U.S. Pat. No. 4,513,146 describes a method for producing esters from highly hindered carboxylic acids and carbonates. The method involves reacting the highly hindered carboxylic acid with a carbonate with or without a catalyst at a temperature of 175xc2x0 C. according to the examples. U.S. Pat. No. 4,513,146 states that exemplary cataysts are nitrogen-containing heterocyclic catalysts such as pyridine, 4-(dimethylamino)pyridine, imidazole, 2,6-lutidine, and 2,4,6-collidine.
Shimizu, I; Lee, Y., Synlett, pg. 1063 (1998) discloses methylation of 1-naphthol with DMC using Na2CO3 which required 168 hours at 120xc2x0 C. for 91% completion. Lissel, M.; Schmidt, S.; Neumann, B., Synthesis, pg. 382 (1986) discloses N-methylation of benzimidazole with DMC using K2CO3 18-crown-6, which required 8 hours at 100xc2x0 C. for 81% yield.
Therefore, it would be advantageous from a production standpoint to develop a more efficient process which utilizes dimethyl carbonate as a reactant in the production of O-methyl phenols, N-methyl heteroaromatic compounds, and methyl aminophenols.
The invention provides an accelerated process for preparing an O-methyl phenol (anisole) comprising reacting a phenol with dimethyl carbonate in the presence of a catalyst selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,4-diazabicyclo[2.2.2]octane; dimethylaminopyridine; and combinations thereof.
According to another aspect, the invention provides an accelerated process for preparing an N-methyl heteroaromatic compound comprising reacting an NH-containing heteroaromatic compound with dimethyl carbonate in the presence of a catalyst selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,4-diazabicyclo[2.2.2]octane; dimethylaminopyridine; and combinations thereof.
According to another aspect, the invention provides an accelerated process for preparing a methylated aminophenol comprising reacting an aminophenol having at least one Nxe2x80x94H with dimethyl carbonate in the presence of a catalyst selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene 1,4-diazabicyclo[2.2.2]octane; dimethylaminopyridine; and combinations thereof.
The process of the invention is especially advantageous for preparing O-methyl phenols, N-methyl heteroaromatic compounds, and methyl aminophenols, since the process: (1) utilizes an environmentally friendly methylating reagent, dimethylcarbonate; (2) produces a high yield of the O-methyl phenols, N-methyl heteroaromatic compounds, and methylated aminophenols, generally 97-100% conversion; and (3) does not require a high-pressure (autoclave) reactor.
The process of the invention is used to prepare an O-methyl phenol and/or an N-methyl heteroaromatic compound, and/or a methylated aminophenol, depending on the choice of reactant. In one embodiment of the invention, the process involves reacting a phenol with dimethyl carbonate to form an O-methyl phenol. As used herein, xe2x80x9cphenolxe2x80x9d refers to a reactant and xe2x80x9cO-methyl phenolxe2x80x9d refers to the product. The phenol may be unsubstituted or substituted with one or more substituent groups or combinations of substituent groups. In addition, the substituent groups attached to the phenol may be combined together with carbon atoms on the phenol to form a 5 to 7 membered aromatic or hetero aromatic ring. Suitable substituent groups on the phenol are groups which do not preclude formation of the O-methyl phenol. Examples of substituent groups on the phenol include, but are not limited to, alkyl, alkenyl, aryl, (cycloalkyl)alkyl, arylalkyl, cycloalkyl, and halogen. Such substituent groups may be unsubstituted or contain groups such as mercapto, hydroxyl, amino, selenyl or carboxyl. When an aryl group or a group containing an aryl portion is used as a substituent group, it may be homocyclic or heterocyclic, and it may comprise a single ring or it may comprise a ring assembly.
Preferred phenols include the following: 
In another embodiment of the invention, the process involves reacting an NH-containing heteroaromatic compound with dimethyl carbonate to form an N-methyl heteroaromatic compound. As used herein, xe2x80x9cNH-containing heteroaromatic compoundxe2x80x9d refers to a reactant having at least one aromatic group and at least one Nxe2x80x94H attached to the aromatic group, and xe2x80x9cN-methyl heteroaromatic compoundxe2x80x9d refers to the product. The NH-containing heteroaromatic compound may be unsubstituted or substituted with one or more substituent groups or combinations of substituent groups. In addition, the substituent groups attached to the NH-containing heteroaromatic compound may be combined together with carbon atoms on the NH-containing heteroaromatic compound to form a 5 to 7 membered aromatic or heteroaromatic ring. Suitable substituent groups on the NH-containing heteroaromatic compound are groups which do not preclude formation of the N-methyl heteroaromatic compound. Examples of substituent groups on the NH-containing heteroaromatic compound include, but are not limited to, alkyl, alkenyl, aryl, (cycloalkyl)alkyl, arylalkyl, cycloalkyl, and halogen. Such substituent groups may be unsubstituted or contain groups such as mercapto, hydroxyl, amino, selenyl or carboxyl. When an aryl group or a group containing an aryl portion is used as a substituent group, it may be homocyclic or heterocyclic, and it may comprise a single ring or it may comprise a ring assembly.
Preferred NH-containing heteroaromatic compounds include the following: 
In another embodiment of the invention, the process involves reacting an aminophenol having at least one Nxe2x80x94H with dimethyl carbonate to form a methylated aminophenol. As used herein, xe2x80x9caminophenol having at least one Nxe2x80x94Hxe2x80x9d refers to a reactant having a phenol group and at least one Nxe2x80x94H directly attached to the aromatic ring of the phenol group, and xe2x80x9cmethylated aminophenolxe2x80x9d refers to the product which contains at least one methoxy or Nxe2x80x94CH3 group. The aminophenol having at least one Nxe2x80x94H may be unsubstituted or substituted with one or more substituent groups or combinations of substituent groups. In addition, the substituent groups attached to the aminophenol having at least one Nxe2x80x94H may be combined together with carbon atoms on the aromatic ring of the phenol group to form a 5 to 7 membered aromatic or hetero aromatic ring. Suitable substituent groups on the aminophenol having at least one Nxe2x80x94H are groups which do not preclude formation of the methylated aminophenol. Examples of substituent groups on the methylated aminophenol include, but are not limited to, alkyl, alkenyl, aryl, (cycloalkyl)alkyl, arylalkyl, cycloalkyl, and halogen. Such substituent groups may be unsubstituted or contain groups such as mercapto, hydroxyl, amino, selenyl or carboxyl. When an aryl group or a group containing an aryl portion is used as a substituent group, it may be homocyclic or heterocyclic, and it may comprise a single ring or it may comprise a ring assembly. A preferred aminophenol having at least one Nxe2x80x94H is m-aminophenol.
The phenol, NH-containing heteroaromatic compound, or aminophenol having at least one Nxe2x80x94H, as described above, are reacted with dimethyl carbonate. Dimethyl carbonate has formula (I) 
The reaction of the phenol, NH-containing heteroaromatic compound, or aminophenol having at least one Nxe2x80x94H with dimethyl carbonate is conducted in the presence of a catalyst which is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); 1,4-diazabicyclo[2.2.2]octane (DABCO); and dimethylaminopyridine (DMAP). A combination of catalysts may also be used.
The equivalent ratio of the catalyst to the phenol, NH-containing heteroaromatic compound, or aminophenol having at least one Nxe2x80x94H, as initially present, is in the range of from about 0.1:1 to about 2:1. More preferably, the equivalent ratio of the catalyst to the phenol, NH-containing heteroaromatic compound, or aminophenol is from about 0.5:1 to about 1:1, most preferably about 1:1.
Preferrably, the process of the invention is conducted at a temperature of from about 10xc2x0 C. to about 300xc2x0 C. More preferably, the process is conducted at a temperature of from about 80xc2x0 C. to 200xc2x0 C.; and most preferably from about 90xc2x0 C. to about 160xc2x0 C. In one embodiment of the invention, microwave irradiation is used to provide the desired reaction temperature. The process is conducted preferably under a pressure of from about 1 atm to about 100 atm, more preferably, from 1 atm to 50 atm. Most preferably, the process is conducted under a pressure of 1 atm.
The process of the invention is preferably conducted in the liquid phase. It may be carried out batchwise, continuously, semibatchwise or semicontinuously. Dimethyl carbonate is generally a liquid under the conditions of the reaction and it may act as a solvent for the phenol, NH-containing heteroaromatic compound, or aminophenol having at least one Nxe2x80x94H. Typically, but not necessarily, excess dimethyl carbonate is employed relative to the amount of phenol, NH-containing heteroaromatic compound, or aminophenol having at least one Nxe2x80x94H. Although extrinsic solvent is not ordinarily employed, it may be used when desired or when necessary to dissolve one or more of the reactants. Examples of suitable extrinsic solvents include: acetonitrile, ethyl acetate, acetone, benzene, toluene, dioxane, dimethylformamide and chlorinated solvents such as chloroform, methylene chloride, ethylene chloride, carbon tetrachloride and chlorobenzene. A combination of solvents may also be used. Preferably, the process is conducted without an extrinsic solvent.
Optionally, the process of the invention may include one or more amine bases. Preferred amine bases are trialkylamines and ethylenediamines. Specific amine bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine and N,Nxe2x80x2-diisopropylethylenediamine. A combination of amine bases may also be used. A preferred amount of amine base is about 1:1 equivalent based on the amount of phenol, NH-containing heteroaromatic compound, or aminophenol having at least one Nxe2x80x94H.
Following preparation, the product of the process, O-methyl phenol, N-methyl heteroaromatic compound, and/or methylated aminophenol may be recovered from the reaction mixture by any of the various techniques known to the art. Distillation at reduced pressure is a preferred technique.
The following nonlimiting examples illustrate further aspects of the invention.